Exploring the causal relationship between dietary macronutrients and neurodegenerative diseases: a bi-directional two-sample Mendelian randomization study

Aim: The associations between dietary macronutrient intake and neurodegenerative diseases (NDDs) have been widely reported; however, the causal effect remains unclear. The current study aimed to estimate the causal relationship between dietary macronutrient intake (i.e., carbohydrate, fat, and protein) and NDDs [e.g., Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS)]. Methods: Mendelian randomization (MR) was applied to evaluate the causal relationship between dietary macronutrient intake and NDDs. We used the single-nucleotide polymorphisms strongly associated (P < 5 × 10-8) with the exposures from the genome-wide association studies as instrumental variables. Inverse-variance weighted, MR-Egger, weighted median, and the MR pleiotropy residual sum and outlier were used to verify the MR assumptions. Results: Genetically predicted higher carbohydrate intake was associated with an increased risk of ALS [odds ratio (OR), 2.741, 95% confidence interval (CI): 1.419-5.293, P = 0.003). Vulnerability to PD was negatively associated with the relative intake of fat (OR, 0.976, 95%CI: 0.959-0.994, P = 0.012) and protein (OR, 0.987, 95%CI: 0.975-1.000, P = 0.042). The study also identified the causal influence of AD on dietary carbohydrate intake (OR, 1.022, 95%CI: 1.011-1.034, P = 0.001). Conclusion: We found solid evidence supporting the idea that a higher carbohydrate proportion causally increases ALS risk. Genetically predicted higher AD risk is causally associated with increased dietary carbohydrate intake. Vulnerability to PD may have a causal relationship with a decrease in the dietary intake of protein and fat.